Crosstalk of factors underlying bone marrow niche-mediated chemoprotection in acute myeloid leukemia

1 Introduction

Acute myeloid leukemia (AML) is an aggressive blood cancer marked by the clonal expansion of immature myeloid progenitor cells in the bone marrow. Despite significant advances in genomic profiling and targeted therapies, after achieving initial complete remission (CR), approximately 40–60% of patients experience disease recurrence, contributing to poor long-term clinical outcomes and an overall 5-year survival of approximately 25–30% (1–3). Leukemogenesis is primarily driven by genetic and epigenetic alterations in hematopoietic stem and progenitor cells (HSPCs) (4). Growing evidence highlights a critical role for the bone marrow (BM) microenvironment in shaping disease (5).

Under normal physiological conditions, the bone marrow (BM) niche maintains hematopoietic stem cell progenitors (HSPCs) in quiescence, supports self-renewal, and promotes differentiation through tightly regulated interactions among cytokines, chemokines, adhesion molecules, and metabolic cues (6). In AML, however, leukemic cells actively reprogram this environment, shifting it from a regulatory system to one that favors malignant persistence and impairs normal hematopoiesis (5). This reprogramming is driven by both soluble factors and direct cell–cell interactions. For example, chemokine signaling via the CXCL12–CXCR4 axis governs leukemic cell homing and spatial localization within protective niches (7), while stromal-derived cytokines such as TGF-β and VEGF activate intracellular survival pathways and remodel vascular architecture (8, 9). Moreover, physical interactions mediated by adhesion receptors and integrins further strengthen the protective effects of the BM niche (10).

In addition to soluble signaling, leukemic cells reshape the niche through extracellular vesicle-mediated communication, metabolic coupling, and vascular remodeling (11). Recent studies further demonstrate that leukemic cells can hijack stromal metabolic programs through mitochondrial transfer and fatty acid oxidation–dependent metabolic adaptation, thereby enhancing survival under therapeutic stress (12, 13). These processes alter stromal cell function, disrupt normal hematopoiesis, and create conditions that favor the maintenance of leukemic stem cells (LSCs). At the same time, immune components within the bone marrow become functionally impaired, with reduced T-cell and natural killer (NK) cell activity contributing to immune escape. Collectively, these changes establish a microenvironment that supports leukemic persistence and limits therapeutic efficacy (14).

In this review, we examine how niche-derived signals regulate leukemic cell behavior, focusing on the molecular mechanisms that govern cell localization, survival, and treatment response. We integrate current understanding of chemokine, cytokine, adhesion, metabolic, and immune pathways, and discuss how these interconnected systems contribute to leukemia progression and chemoprotection. Finally, we highlight emerging therapeutic strategies that disrupt leukemia–microenvironment interactions to improve treatment outcomes.

2 AML niche

The bone marrow (BM) niche is a complex network of cellular components that collectively regulate hematopoietic stem cells (HSCs) and their maintenance and differentiation under normal conditions (6). In AML, this highly organized microenvironment is gradually remodeled to support leukemic cell survival and growth. Several key BM cellular components, including mesenchymal stromal cells, osteoblasts, endothelial cells, immune cells, and adipocytes, contribute to the formation of the AML niche (15).

Mesenchymal stromal cells (MSCs) are crucial components of the bone marrow microenvironment (16). These multipotent stromal cells produce a variety of cytokines, chemokines, and extracellular matrix proteins that support HSPC differentiation (17). In AML, MSCs are often reprogrammed by leukemic cells, adopting a leukemia-supportive phenotype marked by altered cytokine secretion and metabolic activity (16). MSC-derived signals are central to regulating leukemic cells. CXCL12 secreted by MSCs activates CXCR4 on AML cells, triggering the PI3K/AKT and ERK/MAPK pathways, which regulate cell survival, migration, and retention within the niche. In addition, MSC-derived cytokines such as IL-6 activate JAK/STAT signaling, further reinforcing pro-survival and stress-response pathways in leukemic cells (18, 19).

Osteoblasts, which are responsible for bone formation, are another vital component of the niche. Primarily located in the endosteal region of the bone marrow, osteoblasts help regulate HSC quiescence and retention through signaling pathways such as Notch, Wnt/β-catenin, and TGF-β (20). Emerging evidence suggests that leukemic cells can disrupt normal osteoblastic signaling pathways, thereby interfering with the balance between healthy and malignant hematopoiesis (8). In AML, disruption of these pathways alters endosteal niche signaling, reducing normal hematopoietic regulation while indirectly favoring leukemic cell persistence (21).

Endothelial cells form the vascular network within the bone marrow, defining the vascular niche. They regulate the movement of hematopoietic and leukemic cells by secreting chemokines, adhesion molecules, and angiogenic factors (22). Vascular remodeling is common in AML and has been linked to the maintenance of leukemic stem cells and therapy resistance (8). Endothelial cells exert their effects through angiocrine signaling, including the secretion of VEGF and other growth factors that activate the PI3K/AKT and MAPK pathways in leukemic cells. These signals contribute to vascular remodeling and create specialized microenvironments that support leukemic stem cell maintenance and survival (22).

Immune cells in the bone marrow also play an essential role in shaping the leukemic microenvironment (13). T cells, natural killer (NK) cells, macrophages, and myeloid-derived suppressor cells can either promote or inhibit leukemic progression, depending on the context. In many cases, AML niches exhibit immunosuppressive characteristics driven by cytokine signaling pathways. For instance, TGF-β suppresses cytotoxic T-cell and NK cell function, whereas IL-6 and TNF-α activate the JAK/STAT and NF-κB pathways, thereby promoting an immunosuppressive environment that enables leukemic cells to evade immune surveillance (23, 24).

BM adipocytes have recently been identified as important regulators in leukemia biology. These cells supply metabolic substrates, such as lipids and fatty acids, that support the survival and growth of leukemic cells (25). An increase in adipogenic differentiation of stromal cells has been observed in AML and may help leukemic blasts adapt metabolically within the bone marrow environment (26). Adipocyte-mediated effects are largely metabolic, involving the release of fatty acids that leukemic cells utilize via fatty acid oxidation. This metabolic coupling enhances mitochondrial function and provides an alternative energy source, allowing leukemic cells to adapt to nutrient stress and resist therapy-induced metabolic disruption (12, 25, 26).

These cellular components create a complex, dynamic microenvironment that influences leukemic cell behavior through direct cell-to-cell contact and the release of soluble factors (27). Figure 1 illustrates the BM niche in normal vs AML. Collectively, these niche components function through interconnected signaling networks rather than isolated pathways. Chemokine, cytokine, adhesion, and metabolic signals converge on shared intracellular pathways, including PI3K/AKT, NF-κB, and JAK/STAT, which coordinate leukemic cell survival, localization, and adaptation to therapeutic stress (28).

2.1 Leukemic stem cells localization within the bone marrow niche

Leukemic stem cells (LSCs) are a rare yet essential subset of AML cells capable of initiating and sustaining the disease. Like normal hematopoietic stem cells, LSCs rely on signals from the bone marrow microenvironment for their survival and maintenance (29). Accumulating evidence indicates that LSCs occupy distinct microanatomical regions within the bone marrow, primarily the vascular and stromal (endosteal) niches. These niches are not functionally equivalent; rather, they are specialized environments that differentially regulate leukemic stem cell behavior (30).

The endosteal niche, composed of MSC’s, osteoblastic cells, and ECM components, is typically associated with the maintenance of LSC quiescence (31). In this microenvironment, LSCs are retained in a non-proliferative G0 state through signals that limit entry into the cell cycle and promote self-renewal. This “slow-track” niche provides a protective reservoir that enables leukemic stem cells to persist despite therapeutic pressure (5, 15).

In contrast, the vascular niche, formed by endothelial cells lining bone marrow sinusoids and arterioles, is a more dynamic microenvironment that supports leukemic cell activation, proliferation, and trafficking (22). Endothelial cells release signaling molecules and express adhesion receptors that facilitate interactions with leukemic cells, thereby promoting their movement and expansion within the marrow and into the circulation. This “fast-track” niche is therefore more closely associated with actively cycling leukemic cells (32, 33).

This functional dichotomy between niches has significant therapeutic implications. LSCs in the quiescent endosteal niche are inherently less sensitive to cell cycle–dependent chemotherapeutic agents, whereas those in the vascular niche are more likely to be affected by therapies targeting proliferating cells. Together, these specialized microenvironments serve as complementary reservoirs that sustain leukemic stem cell survival, contribute to treatment resistance, and drive disease relapse (29, 30).

3 Molecular interactions between AML cells and the BM niche

The cross-talk between AML cells and the BM niche is mediated by a network of molecular signals that regulate leukemic cell survival, localization, and response to therapy. These interactions involve both soluble factors, such as chemokines, cytokines, and growth factors (34). Direct cell–cell contact is also facilitated through adhesion molecules. Together, these signals enable leukemic cells to exploit the supportive bone marrow microenvironment, thereby promoting their survival and shielding them from chemotherapy. These niche-derived factors and their molecular interactions are therefore crucial for understanding leukemia progression and identifying potential therapeutic targets (5, 8, 15).

3.1 BM niche-related factors in AML

The bone marrow niche regulates leukemic cell behavior through soluble factors and cell-to-cell interactions. These niche-derived signals support AML cell survival and proliferation. The niche also contributes to AML cell retention within protective microenvironments, thereby conferring resistance to therapy. Key mediators include chemokines, cytokines, adhesion molecules, metabolic factors, and extracellular vesicles that activate intracellular pathways favoring leukemic persistence (15). Table 1 summarizes important bone marrow niche-derived factors and their signaling pathways that promote AML cell survival.

Table 1. Niche-related factors in AML.

The key bone marrow niche-derived factors and their signaling pathways that promote AML cell survival.

3.2 Chemokine signaling in AML niche interactions

Chemokines facilitate the interactions between leukemic cells and the bone marrow microenvironment. They control cell migration, tissue homing, and immune cell movement under normal conditions (58). In AML cells, these signaling pathways are exploited to establish stable interactions with the BM niche, enabling cells to remain within protective microenvironments that support survival and resistance to therapy (14). In the past decade, several chemokine signaling axes have been identified as key regulators of AML–niche communication (35). Mechanistically, chemokine signaling regulates cytoskeletal dynamics and cell migration by activating intracellular pathways, thereby controlling leukemic cell positioning within specific niche regions (58).

The CXCL12–CXCR4 chemokine signaling axis is extensively studied and remains a key mechanism controlling leukemic cell homing and retention in the bone marrow (7). CXCL12, also known as stromal-derived factor-1, is continuously secreted by MSCs, osteoblasts, and endothelial cells within the BM. This chemokine establishes a concentration gradient that normally guides HSCs’ migration and positioning. AML blasts often express high levels of the chemokine receptor CXCR4, enabling them to respond strongly to CXCL12 signals in the niche. Activation of CXCR4 triggers intracellular signaling pathways, including PI3K/AKT, ERK/MAPK, and NF-κB, which collectively promote leukemic cell survival, growth, and resistance to apoptosis (35). Among these pathways, PI3K/AKT represents a central survival axis, regulating anti-apoptotic proteins such as BCL-2, while ERK/MAPK contributes to proliferation, and NF-κB reinforces inflammatory and stress-response signaling (59, 60). Clinically, high CXCR4 expression has been associated with poor outcomes and an increased likelihood of relapse, underscoring this pathway’s role in AML progression (7, 35). In addition to CXCR4, AML cells interact with CXCR7. While CXCR4 primarily mediates chemotaxis and cell movement, CXCR7 influences cell survival and adhesion within the bone marrow environment (61). Through these complementary signals, CXCL12 helps maintain leukemic cells within specific niches, thereby evading destruction by therapies and immune responses (35). Functionally, this axis represents the dominant chemokine pathway in AML, integrating migration, retention, and survival signaling within a single regulatory system. Several additional chemokines help establish a leukemia-supportive microenvironment. CCL2, produced by stromal and immune cells, binds to the CCR2 receptor, promoting inflammatory signaling and recruiting monocytes and macrophages to the leukemic niche (38). These immune cells can later develop tumor-supportive traits that enhance leukemic progression. This recruitment contributes to niche remodeling by increasing the abundance of immunosuppressive macrophages, thereby further activating cytokine-driven survival pathways. Similarly, CCL5–CCR5 signaling has been linked to leukemic cell migration and niche retention, further strengthening interactions between AML cells and stromal components (62). CCR5 signaling also interacts with the PI3K/AKT and NF-κB pathways, thereby reinforcing leukemic cell survival and adhesion-dependent signaling (63).

Chemokines produced within the vascular niche also play a crucial role in AML biology. Endothelial cells lining the bone marrow sinusoids secrete CXCL8 (also known as IL-8) (64), CXCL1, and CXCL6, which contribute to angiogenesis and vascular remodeling in the leukemic bone marrow (37, 65). These angiogenic chemokines activate signaling pathways that link inflammation to vascular expansion, further integrating chemokine signaling with the regulation of the endothelial and metabolic niches (55).

Hypoxia in the leukemic marrow further enhances this signaling network, increasing the production of angiogenic chemokines and promoting more extensive niche remodeling (37, 65). Hypoxia-driven stabilization of HIF factors amplifies chemokine expression, thereby strengthening the retention and adaptation of leukemic cells within low-oxygen niches (66).

The immune microenvironment also shapes chemokine signaling within AML niches. Chemokines such as CCL3 and CCL4 mediate inflammatory signaling and recruit immune cells (67, 68), whereas CXCL9 and CXCL10 regulate T-cell trafficking in the bone marrow (69). In AML, these pathways often become dysregulated, creating an immunosuppressive microenvironment that supports leukemic cell survival. This dysregulation alters immune cell recruitment and function, favoring regulatory and suppressive cell populations over effective anti-leukemic responses (23).

In some cases, chemokines may also attract regulatory immune cells that suppress effective anti-leukemia immune responses (67, 69). Importantly, chemokine signaling can mediate protective interactions that directly contribute to drug resistance within the microenvironment. By anchoring AML cells within stromal and vascular niches, chemokines reduce their exposure to cytotoxic agents and activate survival pathways that counteract therapy-induced apoptosis. This retention-based mechanism is a key driver of niche-mediated chemoresistance, directly linking spatial localization to reduced drug sensitivity (13, 29). For this reason, disrupting chemokine signaling has become an important therapeutic strategy. Pharmacological inhibitors of CXCR4, such as plerixafor (AMD3100) and other CXCR4-targeting agents, can mobilize leukemic cells from the bone marrow into the bloodstream, thereby increasing their susceptibility to chemotherapy and targeted treatments (70). Therapeutically, this approach targets leukemic cells’ dependence on niche retention rather than intrinsic survival pathways alone.

Chemokine signaling networks are crucial for organizing the spatial arrangement of leukemic cells within the bone marrow niche. Through coordinated signaling across stromal, vascular, and immune compartments, chemokines create a microenvironment that supports leukemic stem cell survival, drives disease progression, and fosters resistance to therapy. Understanding the complexity of these chemokine networks is therefore essential for developing therapeutic strategies that target leukemia–microenvironment interactions (64, 69). Importantly, chemokine signaling serves as a central organizing axis within the AML niche, integrating migration, adhesion, vascular remodeling, and immune modulation via shared downstream pathways, including PI3K/AKT and NF-κB (71).

3.3 Cytokines and growth factors in the AML leukemic niche

Cytokines and growth factors are vital components of the signaling network that influences the bone marrow microenvironment in acute myeloid leukemia. Normally, these molecules control hematopoietic stem cell survival, growth, and development. But in AML, leukemic cells and surrounding stromal elements create an altered cytokine environment that promotes cancer cell growth while inhibiting normal blood cell production. This cytokine-rich environment not only supports leukemic cell survival but also suppresses the immune system, remodels the niche, and induces treatment resistance (41). One significant cytokine involved in AML–niche interactions is transforming growth factor-β (TGF-β). TGF-β is produced by stromal cells, immune cells, and sometimes by leukemic blasts themselves. In the bone marrow niche, this cytokine regulates cell growth and development by activating SMAD signaling pathways (39). In the leukemic environment, TGF-β signaling leads to immune suppression and promotes leukemic cell survival. Studies show that blocking TGF-β signaling can make AML cells more sensitive to chemotherapy, highlighting its role in microenvironment-driven chemoresistance (39). TGF-β signaling primarily acts through SMAD-dependent transcriptional regulation, suppressing immune cell activation and promoting a more quiescent cellular state. This shift toward reduced proliferation contributes to decreased sensitivity to cytotoxic therapies, particularly those targeting actively dividing cells (72). Angiogenic factors are also important in AML niche biology, especially vascular endothelial growth factor (VEGF) (9). VEGF is produced by leukemic blasts, stromal, and endothelial cells in the bone marrow. By activating VEGF receptors on endothelial and leukemic cells, this pathway promotes new blood vessel formation and vascular remodeling within the marrow (9). Increased vascular density is often observed in AML bone marrow, helping leukemic stem cells survive by creating specialized vascular niches rich in growth factors and oxygen gradients. VEGF-mediated signaling activates PI3K/AKT and MAPK pathways in both endothelial and leukemic cells, linking angiogenesis directly with survival signaling. This dual role positions the vascular niche as both a structural and functional regulator of leukemic cell maintenance (73). Inflammatory cytokines also play a major role in shaping the leukemic microenvironment (9). Tumor necrosis factor-α (TNF-α) is produced by leukemic cells and stromal components. It contributes to inflammatory remodeling of the BM niche. TNF-α signaling affects endothelial cell function, leading to vascular niche remodeling and regulation of leukemic stem cells. Additionally, TNF-α can activate NF-κB signaling pathways, thereby promoting leukemic cell survival and resistance to apoptosis (68). At the signaling level, TNF-α activates NF-κB, a key transcriptional regulator of inflammatory and survival gene programs. NF-κB activation enhances expression of cytokines, adhesion molecules, and anti-apoptotic factors, creating a feed-forward loop that sustains both niche remodeling and leukemic cell persistence (74). Another cytokine often elevated in the AML microenvironment is interleukin-6 (IL-6). IL-6 is secreted by stromal cells, macrophages, and other immune cells within the BM niche. This cytokine activates the JAK/STAT signaling pathway, thereby increasing leukemic cell growth and survival. Higher IL-6 levels are linked to inflammatory signaling within the leukemic niche. It drives leukemia by boosting cell proliferation and protecting cells from stress-induced apoptosis. Growth factors that regulate hematopoiesis also influence AML niche behavior (42). Colony-stimulating factor-1 (CSF-1) and other hematopoietic growth factors affect macrophage development and immune cell recruitment in the bone marrow. As a result, they help create a tumor-supportive immune microenvironment that favors the persistence of leukemic cells (43). Mechanistically, IL-6 signaling is one of the dominant cytokine axes in AML, as activation of JAK/STAT3 leads to the transcription of anti-apoptotic genes such as BCL-2 and MCL-1, as well as regulators of cell cycle progression. This pathway also functionally overlaps with PI3K/AKT signaling, thereby reinforcing survival under therapeutic stress and positioning IL-6 as a central mediator of niche-driven resistance (75).

Several soluble mediators produced by stromal cells regulate leukemic cell survival and metabolic adaptation. Prostaglandins derived from stromal cyclooxygenase-2 (COX-2) activity modulate inflammatory signaling pathways and immune cell function within the niche. These mediators link inflammatory signaling to metabolic changes in stromal cells and further promote leukemia-supportive conditions in the bone marrow (50).

Cytokines and growth factors coordinate to form a complex signaling network that links leukemic cells to the stromal, vascular, and immune components of the bone marrow microenvironment. By activating pathways such as JAK/STAT, NF-κB, PI3K/AKT, and SMAD signaling, these molecules regulate leukemic cell growth, survival, immune evasion, and therapy resistance (19, 72). Understanding how cytokine signaling shapes the leukemic niche is crucial for developing treatments that target interactions within this protective microenvironment and improve outcomes in AML (41). Importantly, these cytokine and growth factor pathways do not function independently but converge on shared intracellular signaling axes, particularly JAK/STAT, PI3K/AKT, and NF-κB. This convergence amplifies downstream survival signaling and integrates inflammatory, metabolic, and adhesion-mediated inputs within the leukemic niche (57, 75).

3.4 Stromal cell remodeling in the AML microenvironment

MSCs are among the most important stromal cell populations in the bone marrow niche. Under normal conditions, MSCs regulate hematopoietic stem cell maintenance by secreting chemokines such as CXCL12 and producing extracellular matrix proteins and growth factors (7, 35). However, in AML, MSCs often exhibit altered transcriptional and metabolic profiles, including increased production of inflammatory cytokines and altered extracellular matrix remodeling. AML cells actively prime MSCs toward a pro-inflammatory secretory phenotype characterized by increased production of interleukin-6 (IL-6), interleukin-8 (IL-8), and CCL2. This inflammatory secretome establishes a self-reinforcing signaling loop that enhances leukemic cell retention, survival, and chemoresistance by activating the JAK/STAT and NF-κB pathways (38, 42). These changes create a microenvironment that favorably supports leukemic cell survival and growth. Mechanistically, CXCL12–CXCR4 signaling activates PI3K/AKT and ERK pathways in leukemic cells, regulating cell survival, migration, and retention within the niche. In parallel, inflammatory cytokines secreted by MSCs activate the JAK/STAT and NF-κB pathways, thereby reinforcing anti-apoptotic signaling. AML also disrupts typical stromal differentiation pathways (16). MSCs normally differentiate into osteoblasts, adipocytes, and chondrocytes, but leukemic cells can skew this balance toward lineages that promote leukemic growth. Increased adipogenic differentiation has been reported in AML bone marrow, and adipocytes can supply metabolic substrates, such as fatty acids, that sustain leukemic cell metabolism and survival (26).

Inflammatory signaling also drives stromal remodeling. Leukemic blasts and stromal cells secrete cytokines, including TNF-α and interleukins, that activate survival pathways, including NF-κB and JAK/STAT signaling (68). In some cases, stromal cells acquire features of cellular senescence and develop a senescence-associated secretory phenotype (SASP), characterized by increased secretion of inflammatory mediators that reinforce leukemic progression (51). NF-κB signaling acts as a central regulator in this context, promoting the transcription of cytokines, adhesion molecules, and anti-apoptotic proteins, thereby sustaining a chronic inflammatory and leukemia-permissive microenvironment (57, 74).

Metabolic interactions between stromal and leukemic cells also contribute to niche remodeling. Stromal cells supply metabolites, including amino acids and lipids, that leukemic cells use for energy and biosynthesis. Additionally, direct adhesion between leukemic blasts and stromal cells via integrins and other adhesion molecules activates survival signaling pathways and contributes to cell-adhesion-mediated drug resistance (CAM-DR). Integrin engagement activates intracellular kinases such as Syk, which further stimulate STAT and PI3K/AKT signaling, linking adhesion directly to anti-apoptotic pathways and reduced chemotherapy sensitivity (76).

Overall, stromal remodeling is an essential mechanism by which AML cells reshape the bone marrow niche to support leukemic survival, resistance to therapy, and disease progression (48). Importantly, these processes are highly interconnected, with chemokine, cytokine, metabolic, and adhesion-mediated signals converging on shared pathways such as PI3K/AKT, NF-κB, and JAK/STAT, forming an integrated network that sustains leukemic cell adaptation within the niche (75).

3.5 Extracellular vesicles and exosome-mediated niche communication in AML

Extracellular vesicles (EVs) have become key mediators of communication between leukemic cells and the bone marrow microenvironment. These membrane-bound vesicles carry proteins, lipids, and nucleic acids that can influence the behavior of recipient cells. Among them, exosomes (30–150 nm) play a particularly important role in leukemia biology. AML cells release large numbers of EVs that are taken up by stromal, endothelial, and immune cells within the bone marrow (49). Mechanistically, EV uptake occurs via endocytosis or membrane fusion, enabling the direct transfer of regulatory molecules, such as microRNAs and proteins, that alter intracellular signaling pathways in recipient cells (77). The molecular cargo delivered by these vesicles modifies gene expression in recipient cells and promotes the formation of a leukemia-supportive microenvironment. AML-derived exosomes alter stromal cell behavior, leading to increased secretion of growth factors and inflammatory cytokines that support leukemic proliferation (77, 78). Importantly, this process reflects a bidirectional crosstalk in which AML cells actively reprogram healthy mesenchymal stromal cells into leukemia-supportive stromal elements. Through exosomal transfer of regulatory molecules, leukemic blasts induce transcriptional and metabolic changes in stromal cells, promoting inflammatory signaling, extracellular matrix remodeling, and enhanced secretion of niche-supportive factors (78). This reprogramming is driven by EV-associated microRNAs and transcriptional regulators that activate signaling pathways such as NF-κB and JAK/STAT, resulting in sustained production of pro-inflammatory and pro-survival factors. Several exosomal microRNAs, including miR-155 and miR-150, have been implicated in stromal reprogramming and inflammatory niche remodeling in AML (79). These regulatory molecules alter pathways involved in cytokine production, hematopoietic support, and metabolic regulation, thereby disrupting normal niche function and favoring leukemic persistence. They suppress normal hematopoiesis by delivering microRNAs that interfere with transcription factors involved in hematopoiesis. For example, EV-mediated transfer of specific microRNAs can downregulate key hematopoietic regulators, disrupting differentiation programs and favoring leukemic dominance within the niche (48, 49).

Additionally, EVs contribute to immune modulation within the leukemic niche. AML-derived vesicles can inhibit T-cell proliferation and reduce NK cell cytotoxicity, thereby promoting immune evasion. This immunosuppressive effect is mediated by modulation of immune signaling pathways, including suppression of activation signals and induction of inhibitory receptor pathways in T cells and NK cells (24). Circulating EVs have also been detected in the peripheral blood of AML patients, suggesting a potential role in systemic communication and disease progression. These circulating vesicles may precondition distant microenvironments or reinforce systemic immune suppression, extending the impact of leukemic signaling beyond the bone marrow. EVs contribute to niche remodeling, immunosuppression, and therapy resistance; they are increasingly being explored as potential therapeutic targets and biomarkers in AML (49). Importantly, EV-mediated signaling integrates with chemokine, cytokine, and adhesion pathways, converging on shared intracellular axes such as NF-κB and PI3K/AKT, thereby amplifying leukemic cell adaptation and resistance to therapy (11, 49).

3.6 Adhesion and integrin signaling in the AML niche

Direct interactions between leukemic cells and the bone marrow microenvironment are central to AML progression. Adhesion molecules on AML blasts enable attachment to stromal and endothelial cells and to extracellular matrix components, anchoring them within protective niches (45). These interactions are mediated by adhesion receptors such as integrins, CD44, and selectins, which not only facilitate physical retention but also initiate intracellular signaling cascades that regulate leukemic cell behavior. For example, binding of very late antigen-4 (VLA-4) on leukemic cells to vascular cell adhesion molecule-1 (VCAM-1) on stromal cells activates PI3K/AKT signaling, leading to enhanced anti-apoptotic responses and increased resistance to chemotherapy. Similarly, E-selectin-mediated interactions contribute to leukemic cell retention and survival within vascular niches (45, 80).

Integrins play a critical role in mediating these interactions. These transmembrane receptors enable leukemic cells to bind extracellular matrix proteins such as fibronectin and collagen, thereby facilitating close contact with stromal cells. Beyond providing structural support, integrin engagement triggers intracellular signaling pathways that regulate leukemic cell survival and growth. β2-integrins activate Syk–STAT signaling, which boosts leukemic cell survival and proliferation (44). Moreover, integrin signaling interacts with the PI3K/AKT, MAPK, and NF-κB pathways, further promoting pro-survival signals within the niche. These adhesion interactions contribute to cell adhesion-mediated drug resistance (CAM-DR). When AML cells adhere to stromal cells or extracellular matrix components, anti-apoptotic pathways are activated, reducing the effectiveness of chemotherapy. Additionally, stromal niches can physically shield leukemic cells from drug exposure, allowing residual leukemic stem cells to survive and eventually cause disease relapse (10, 44, 45).

3.7 Vascular niche remodeling in AML

The bone marrow vascular network creates a crucial regulatory niche that influences both hematopoiesis and leukemic progression. The vascular niche undergoes notable remodeling that supports leukemic cell survival in AML. AML bone marrow often shows increased angiogenesis and vascular density due to leukemic cells secreting pro-angiogenic factors such as VEGF and b-FGF (9). Mechanistically, VEGF signaling activates VEGFR-dependent PI3K/AKT and MAPK pathways in endothelial and leukemic cells, linking angiogenesis directly to survival and proliferative signaling (73). These new vessels supply nutrients and form specialized microenvironments that help sustain leukemic stem cells. In addition to nutrient delivery, these vascular niches provide localized gradients of chemokines and oxygen that regulate leukemic cell positioning and metabolic adaptation. Vascular remodeling also involves changes in the balance between arteriolar and sinusoidal vessels. Studies report a decrease in arteriolar structures alongside an expansion of sinusoidal vessels, which may affect leukemic cell trafficking and survival. Endothelial cells actively influence leukemic stem cell behavior through the release of chemokines and growth factors (9). These angiocrine signals activate pathways such as CXCL12–CXCR4 and PI3K/AKT, reinforcing leukemic stem cell maintenance and niche retention (36). Endothelial miR-126 has been linked to the maintenance of leukemic stem cells. Mechanistically, miR-126 regulates signaling networks associated with cell-cycle control and quiescence, thereby enabling leukemic stem cells to persist in a low-proliferative, therapy-resistant state (54).

Hypoxia and inflammatory cytokines further enhance vascular remodeling by encouraging angiogenesis and altering endothelial cell function. Hypoxia stabilizes hypoxia-inducible factors (HIF-1α and HIF-2α), which upregulate angiogenic genes and metabolic pathways, while inflammatory cytokines activate NF-κB signaling to sustain vascular and niche remodeling. Collectively, vascular remodeling integrates angiogenic, metabolic, and chemokine signaling, converging on pathways such as PI3K/AKT and NF-κB to create a protective niche that supports leukemic persistence and limits therapeutic efficacy (81, 82).

3.8 Hypoxia and metabolic niches in AML

The bone marrow naturally contains low-oxygen areas that regulate hematopoietic stem cell function. In AML, rapid leukemic cell growth increases oxygen consumption, creating more hypoxic regions in the marrow (37). This oxygen imbalance stabilizes hypoxia-inducible factors (HIF-1α and HIF-2α), which act as transcriptional regulators of metabolic adaptation and cellular stress responses. Hypoxia triggers the expression of hypoxia-inducible factors (HIF-1α and HIF-2α), which regulate genes involved in metabolism, blood vessel formation, and cell survival. HIF activation induces the expression of glycolytic enzymes and angiogenic factors, such as VEGF, linking metabolic reprogramming to vascular remodeling. AML cells adapt to these conditions by increasing glycolysis and altering mitochondrial metabolism, helping them survive metabolic stress. This shift toward glycolysis, often referred to as metabolic reprogramming, is supported by HIF-driven transcription and coordinated with PI3K/AKT/mTOR signaling, which integrates nutrient sensing with cell growth. Interactions with stromal cells also support leukemic survival (81). These stromal cells can supply amino acids, lipids, and other nutrients that leukemic cells use for energy. This metabolic coupling enables leukemic cells to maintain biosynthetic activity under nutrient-limited conditions and enhances resistance to metabolic stress. Bone marrow fat cells are another key energy source, providing fatty acids that support leukemic cell metabolism and stem cell maintenance. Fatty acids are utilized via fatty acid oxidation pathways, thereby enhancing mitochondrial function and supporting the long-term maintenance of leukemic stem cells (25). Cells in hypoxic niches often show reduced sensitivity to chemotherapy, partly due to slower growth and activation of survival mechanisms. Hypoxia-associated quiescence reduces the effectiveness of therapies targeting proliferating cells, while HIF-dependent signaling activates anti-apoptotic pathways that further limit drug response. These metabolic niches create conditions that favor leukemic persistence and contribute to disease relapse (37, 81). Importantly, hypoxia-driven metabolic reprogramming integrates with cytokine, adhesion, and vascular signaling, converging on pathways such as PI3K/AKT and HIF-mediated transcription to sustain leukemic cell adaptation within the niche (82).

3.9 Immune microenvironment in AML

The bone marrow immune microenvironment plays a crucial role in regulating leukemic progression. In AML, immune cells often become functionally impaired or reprogrammed to support the growth of malignant cells rather than eliminate them. Multiple immune cell types contribute to the AML niche, including T cells, natural killer (NK) cells, macrophages, dendritic cells, and myeloid-derived suppressor cells (MDSCs) (13). This reprogramming is driven by cytokine- and chemokine-mediated signaling that alters immune cell activation, differentiation, and effector functions within the niche (19). Leukemic cells release cytokines, chemokines, and extracellular vesicles that alter immune cell function and promote immune suppression. These factors activate intracellular signaling pathways such as JAK/STAT and NF-κB in immune cells, shifting them toward immunosuppressive phenotypes (13, 57).

T cells in AML often show signs of exhaustion, marked by reduced proliferation and impaired cytokine production. This exhausted state is linked to altered signaling through inhibitory pathways and diminished activation of effector transcriptional programs. A major driver of this phenotype is activation of the programmed cell death protein 1 (PD-1)/PD-L1 immune checkpoint axis. AML blasts and stromal cells can express PD-L1, which binds PD-1 on T cells and suppresses downstream activation signaling, thereby reducing T-cell proliferation, cytokine production, and cytotoxic activity (83). Regulatory T cells are often increased, further suppressing anti-leukemic immune responses. These cells suppress immune activation through cytokine-mediated mechanisms, including TGF-β signaling, which inhibits effector T-cell function. NK cells, which normally target and destroy malignant cells, are also inhibited within the leukemic microenvironment. Cytokines such as TGF-β suppress NK-cell cytotoxicity and impair their ability to recognize leukemic targets. At the molecular level, TGF-β signaling reduces expression of activating receptors and cytotoxic mediators in NK cells, thereby limiting their anti-leukemic activity (39).

Macrophages in the AML bone marrow often resemble tumor-associated macrophages (TAMs) (64), which promote leukemic cell survival. These macrophages secrete cytokines such as IL-6, TNF-α, and TGF-β and inhibit T- and NK-cell activity, thereby aiding immune evasion (39, 42, 84). MDSCs enhance immune suppression by blocking T-cell activation through reactive oxygen species and immunosuppressive cytokines (24). These cytokines activate the JAK/STAT and NF-κB signaling pathways, thereby reinforcing both inflammatory signaling and anti-apoptotic programs in leukemic cells. In addition to cytokine-mediated suppression, AML cells also alter the metabolic landscape of the bone marrow niche. Rapid leukemic proliferation increases competition for nutrients such as glucose and amino acids, limiting their availability to T cells and reducing their metabolic fitness and effector function. Accumulation of metabolic by-products, such as lactate, within the niche further contributes to impaired immune activation and the persistence of an immunosuppressive microenvironment (74, 75). Furthermore, molecules like galectins and AML-derived extracellular vesicles contribute to immune dysfunction within the bone marrow niche. Galectin-mediated signaling modulates immune checkpoint pathways, while extracellular vesicles transfer regulatory molecules that further suppress immune cell activation and cytotoxicity. Importantly, immune suppression in AML is not an isolated process but is tightly integrated with chemokine, cytokine, and metabolic signaling networks. These pathways converge on shared intracellular axes such as JAK/STAT and NF-κB, collectively shaping an immunosuppressive niche that limits effective anti-leukemic responses (52, 53).

4 Role of niche-derived factors in chemoprotection

One of the major challenges in AML treatment is the persistence of leukemic cells despite an initial therapeutic response, ultimately leading to relapse and poor long-term outcomes. Increasing evidence indicates that these chemoprotective effects are strongly mediated by interactions between leukemic cells and the bone marrow microenvironment. Through coordinated stromal, vascular, immune, and metabolic signaling, niche-derived factors establish a highly adaptive microenvironment that enables leukemic cell persistence under therapeutic stress (9, 29, 30, 80). These factors not only regulate leukemic stem cell survival and quiescence but also facilitate their retention within specialized bone marrow niches, thereby limiting effective drug exposure and promoting minimal residual disease. Among the major mechanisms contributing to niche-mediated chemoresistance is CAM-DR. Adhesion molecules such as integrins, VLA-4, VCAM-1, CD44, and E-selectin activate intracellular survival pathways, including PI3K/AKT, NF-κB, and MAPK signaling, thereby suppressing chemotherapy-induced apoptosis and enhancing leukemic cell survival (76). In parallel, hypoxic regions within the bone marrow stabilize hypoxia-inducible factors (HIF-1α and HIF-2α), promoting leukemic stem cell quiescence, metabolic adaptation, and reduced sensitivity to cell cycle–dependent chemotherapy (82). Stromal cells and adipocytes further contribute to metabolic protection by supplying amino acids, lipids, and fatty acids that sustain mitochondrial metabolism and fatty acid oxidation under chemotherapeutic stress. Importantly, these mechanisms function as an interconnected signaling network rather than isolated pathways (16, 25, 26). Chemokine signaling through the CXCL12–CXCR4 axis, inflammatory cytokine signaling mediated by JAK/STAT and NF-κB pathways, and extracellular vesicle-mediated stromal reprogramming collectively reinforce leukemic cell retention, immune evasion, metabolic adaptation, and therapy resistance within the bone marrow niche (18, 36, 57, 75). Among these mechanisms, the CXCL12–CXCR4, PI3K/AKT, NF-κB, and JAK/STAT pathways emerge as central regulatory hubs that integrate adhesion signaling, inflammatory responses, metabolic adaptation, and leukemic stem cell persistence within protective marrow niches (36, 75). A detailed summary of niche-derived factors and their contribution to chemoresistance is provided in Table 2.

Table 2. Major bone marrow niche-derived signaling pathways contributing to chemoresistance in acute myeloid leukemia (AML).

The table summarizes key stromal, vascular, immune, metabolic, and hypoxia-associated factors that contribute to leukemic cell retention, survival signaling, immune evasion, metabolic adaptation, and chemotherapy resistance within the bone marrow microenvironment.

5 Therapeutic targeting of the AML niche

Because the bone marrow microenvironment plays a crucial role in supporting leukemic cell survival and drug resistance, therapies that disrupt leukemia–niche interactions are increasingly gaining attention. One key strategy targets the CXCL12–CXCR4 signaling axis, which anchors leukemic cells within protective bone marrow niches. CXCR4 inhibitors, such as plerixafor (AMD3100), can mobilize leukemic cells into the peripheral blood, thereby making them more vulnerable to chemotherapy and targeted therapies (70). In addition to blocking chemokine signaling, researchers are exploring ways to interfere with stromal-derived survival signals. Approaches like JAK inhibitors, as well as inhibitors targeting prostaglandin and galectin signaling, aim to weaken supportive signals from stromal cells (16, 80). The vascular niche is another promising therapeutic target since endothelial cells provide factors essential for maintaining leukemic stem cells and promoting therapy resistance. Lastly, strategies to restore immune function are being actively studied, including immune checkpoint inhibitors and CAR-T cell–based therapies, which aim to enhance immune recognition and destruction of leukemic cells (88). Collectively, these approaches demonstrate a growing focus on therapies that target not only leukemic cells but also the supportive bone marrow niche that sustains disease progression and relapse. Table 3 summarizes the niche targets and key pathways associated with drugs used for treatment, along with their therapeutic goals.

Table 3. Therapeutic strategies targeting bone marrow niche interactions in AML.

6 Discussion

Over the past decade, our understanding of acute myeloid leukemia (AML) has shifted from a leukemia-cell-centric view to one that recognizes the bone marrow microenvironment as an active, dynamic regulator of disease biology. Rather than a passive structural compartment, the bone marrow niche functions as a highly interconnected ecosystem comprising stromal, vascular, immune, and metabolic components that collectively influence leukemic stem cell behavior, therapeutic response, and disease progression. Increasing evidence indicates that AML cells actively remodel this microenvironment through bidirectional crosstalk mediated by cytokines, chemokines, adhesion receptors, extracellular vesicles, and metabolic signaling pathways (101).

A major theme emerging from recent studies is that niche-mediated signaling pathways do not act in isolation but instead converge into integrated regulatory networks that sustain leukemic persistence. Among these, the CXCL12–CXCR4, PI3K/AKT, NF-κB, and JAK/STAT pathways appear to serve as central signaling hubs linking leukemic cell retention, inflammatory signaling, metabolic adaptation, immune suppression, and resistance to apoptosis (7, 59, 74, 75). Stromal reprogramming driven by the AML-derived inflammatory secretome and by extracellular vesicle–mediated transfer of regulatory molecules promotes the establishment of leukemia-permissive niches characterized by enhanced cytokine production, extracellular matrix remodeling, and altered hematopoietic support. Similarly, vascular remodeling and hypoxia-associated signaling create specialized microenvironments that maintain leukemic stem cell quiescence and reduce sensitivity to cell cycle–dependent chemotherapy (42, 80).

Metabolic crosstalk has also emerged as a critical component of leukemic niche biology. AML cells not only consume nutrients from stromal cells and adipocytes but also actively hijack metabolic programs through fatty acid oxidation, mitochondrial transfer, and adaptation to hypoxic stress. These mechanisms enhance bioenergetic flexibility and promote leukemic survival under therapeutic stress. In parallel, immune dysfunction within the bone marrow microenvironment further contributes to leukemic persistence. T-cell exhaustion, NK-cell suppression, immune checkpoint activation, and immunosuppressive cytokine signaling collectively impair anti-leukemic immune responses and reinforce a protective niche state (13, 23, 24, 87).

The persistence of leukemic stem cells within specialized microenvironments remains a major challenge in AML therapy. Their ability to remain quiescent, metabolically adaptable, and protected within niche compartments contributes significantly to minimal residual disease and relapse. Consequently, therapeutic strategies aimed at disrupting leukemic niche interactions have increasingly attracted attention, including inhibition of CXCL12–CXCR4 signaling, blockade of adhesion-mediated survival pathways, targeting of metabolic dependencies, and restoration of anti-leukemic immune function. Although several niche-targeting strategies have shown promising preclinical and early clinical results, the heterogeneity and plasticity of the AML microenvironment remain major obstacles to durable therapeutic responses (18, 35, 36).

Despite substantial advances, many aspects of AML niche biology remain incompletely understood. The composition and functional behavior of the leukemic microenvironment likely vary across AML subtypes, disease stages, and treatment conditions. Emerging technologies, including single-cell sequencing, spatial transcriptomics, metabolomics, and high-resolution imaging, are now providing unprecedented insight into the leukemic niche’s spatial and molecular organization. These approaches may help identify subtype-specific vulnerabilities and enable the development of more precise, microenvironment-targeted therapeutic strategies.

In summary, the bone marrow microenvironment plays a central role in shaping AML progression, chemoresistance, immune evasion, and disease relapse. The dynamic, bidirectional crosstalk between leukemic cells and niche components creates a highly adaptive ecosystem that supports leukemic persistence under therapeutic pressure. A deeper mechanistic understanding of these interconnected signaling networks will be essential to designing next-generation therapeutic approaches that simultaneously target leukemic cells and the supportive microenvironment that sustains them.

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Footnotes

Edited by: Kathryn A Skelding, The University of Newcastle, Australia

Reviewed by: Shahrzad Mousavi, Tarbiat Modares University, Iran

Hamenth Kumar Palani, Christian Medical College and Hospital, India